5-azido-laevulinic acid, method for the production thereof and its use

ABSTRACT

The present invention relates to 5-azido levulinic acid, a process for its preparation, its use. Using 5-azido levulinic acid as starting material for the synthesis of 5-amino levulinic acid hydrochloride it is possible to obtain the latter in good yield an in pharmaceutical acceptable quality. 5-Azido levuliniv acid is synthesized in that methyl 5-bromo levulinate and/or methyl 5-chloro levulinate is converted with aqueous hydrochloric acid and as a result of an incomplete bromine/chlorine exchange at the C-5-postion a mixture of 5-chloro levulinic acid and 5-bromo levulinic acid is obtained, and the obtained 5-chloro levulinic acid, a mixture of 5-chloro levulinic acid and 5-bromo levulinic acid and the pure 5-bromo levulinic acid is transferred into 5-azido levulinic acid by conversion with a nucleophilic azide.

The present invention relates to 5-azido levulinic acid, a process forits preparation, its use for the preparation of 5-amino levulinichydrochloride, and its use as explosive.

The importance of 5-amino levulinic acid hydrochloride as startingmaterial for the synthesis of various compounds as well as its manifoldemployment, especially in the field of medicine, will be explainedbelow.

5-Amino levulinic acid, storable as its halogen acid addition salt, inparticular 5-amino levulinic acid hydrochloride, is a bioorganiccompound, which appears as preliminary stage on the tetrapyrrolebiosynthetic pathway of porphobilinogene, chlorophylle, haemine,vitamine B₁₂, and cytochrome (K. D. Gibson et al., Biochem. J. 1955, 61,618; S. I. Beale, Plant Physiol. 1971, 48, 316; C. A. Rebeiz, PlantPhysiol. 1970, 46, 543; A. I. Scott, Angew. Chem. 1993, 105, 1281-1302;Angew. Chem. Int. Ed. Engl. 1993, 32, 1223).

As known, these compound or its alkyl esters will be used as startingcompound in the synthesis of a multitude of compounds.

5-Amino levulinic acid hydrochloride is used as substrate for the assayof 5-amino levulinic acid dehydratase (D. Shemin et al., MethodsEnzymol. 1970, 17(A), 205; D. L. Coleman, ibid. 211; A. M. del C. Beatleet al., ibid., 216; P. Bodlaender et al., Anal. Biochem. 1974, 58, 500;D. Gurne, D. Shemin, Methods Enzymol. 1976, 44, 844), in acriculture asselective herbicide (5-amino levulinic acid hydrochloride: C. A. Rebeizet al., Enzyme Microb. Technol. 1984, 6, 390; Chem. & Eng. News 1984,62, 8; S. O. Duke, C. A. Rebeiz, Porphyric Pesticides: Chemistry,Toxikology, and Pharmaceutical Applications. ACS Symposium Series 5591994; alkyl esters of 5-amino levulinic acid hydrochloride: H. Takeya,Jpn. Kokai Tokkyo Koho JP 0409360, 1992; Chem. Abstract. 1992, 116,19755), as insecticide (C. A. Rebeiz et al., Pestic. Biochem. Physiol.1988, 30, 11; A. I. Scott, Angew. Chem. 1993, 105, 1281-1302; Angew.Chem. Int. Ed. Engl. 1993, 32, 1223; S. O. Duke, C. A. Rebeiz, PorphyricPesticides: Chemistry, Toxikology, and Pharmaceutical Applications. ACSSymposium Series 559 1994), and in various fields of medicine.

In the field of medicine, in particular the field of oncology, 5-aminolevulinic acid hydrochloride is used for the treatment of actinicceratosis with the help of photodynamic therapy (PDT) (Drugs Fut. 2000,25(1), 74-76 and cited literature therein).

But also in photodynamic diagnostics (PDD), this includes someapplications of the PDT, i.e. the fluorescence detection of some kindsof cancer like lung cancer, bladder cancer, and prostate cancer (WO93/20810, WO 96/39188, WO 98/09155; A. G. Hofstetter, Springer Verlag,Berlin, Heidelberg, New York, London, Paris, Tokio, Hong Kong,Barcelona, Budapest, 1995.), as well as in marking brain tumors (W.Stummer et al., Neurosurgery 1998, 42(3), 518-526.) someone fall back on5-amino levulinic acid hydrochloride.

A novel application concerns the photosensitation of arteries incombination with the baloon anglioplastics, which shall make anoperative post treatment with hardening of the arteries unnecessary (NewScientist 1999, 162, Nr. 2185).

Recently, there was reported about the application of 5-amino levulinicacid hydrochloride as hair restorer (Shiseido Co., Ltd.; Cosmo SogoKenkyusho K. K., Jpn. Kokai Tokkyo Koho JP 11116, 446 [99116, 446],1999; Chem. Abstract. 1999, 130, 356898z).

The big interest in 5-amino levulinic acid hydrochloride is alsoreflected by the great number of synthetic pathways described in theliterature.

The discussion of the various processes must follow in view of thetransferness to the technical production scale, so that this compound,which is useful in so many fields, can be prepared on a large scale,cost-effective and without pollution of the environment.

Some exemplary production processes of 5-amino levulinic acidhydrochloride, starting from different substance classes are discussedin the following.

U.S. Pat. No. 5,380,935 discloses a process, in which furfuryl amine,the amino function of which was protected, is oxidised by oxygen on thephotochemical pathway in the precense of a sensetizer. Catalyticreduction of the intermediate and subsequent acid catalysed deprotectionof the resulting product yielded 5-amino levulinic acid hydrochloride.

Some other processes make use of furane derivatives as starting materialfor the synthesis of 5-amino levulinic acid hydrochloride, also (EP-A0607952; U.S. Pat. No. 5,284,973; U.S. Pat. No. 5,344,974; L. Cottier,G. Descotes, L. Eymard, K. Rapp, Synthesis 1995, 303-306; K. Suzuki etal., Nippon Kagaku Kaishi 1999, 3, 199-202).

All these processes have a great deal in common: The amino function hasto be protected first, and in the last step of the synthetic sequencethe protecting group has to be removed again. Partly, for the user andthe environment, harmful solvents and chemicals are used, which have tobe disposed cost-intensive after the reaction.

The use of expensive photosensetizers like fullerene (C60) or rosebengal is to be said against a technical application of these processes,too.

Alternatively, some succinyl derivatives—by introduction of ancarbon-nitrogen moiety—are used for the synthesis of 5-amino levulinicacid hydrochloride.

In U.S. Pat. No. 3,846,490, e.g. mono methyl succinate mono chloride wasreacted together with hippuric acid in γ-picoline as solvent. Theobtained oxazolidine derivative is hydrolised with formation of 5-aminolevulinic acid hydrochloride. Further processes, which start fromsuccinic acid, are described by A. Pfaltz, Tetrahedron Lett. 1984, 25,2977-2980 and A. Nudelman, A. Nudelman, Synthesis 1999, 5, 568-570.

Unfortunately, the single workup steps of these reaction sequences areexpensive and result in side products, which have to be seperated. Forthe preparation of 5-amino levulinic acid hydrochloride according to theprocesses described here, toxic chemicals (i.e. zinc, copper cyanide)and solvents (i.e. γ-picoline) are used. The toxic side products, builtup in parts of the synthesis, have to be disposed.

As well, pyridine derivatives are used as starting material for thesynthesis of 5-amino levulinic acid hydrochloride. Starting from2,5-dihydroxy pyridine, C. Herdeis et al. (Arch. Pharm. 1984, 317,304-306) obtained a product by oxidation. Subsequent catalytichydrogenation yielded 2,5-piperidone, which was converted into 5-aminolevulinic acid hydrochloride by acidic hydrolysis. H. Takeya, K. Suzuki,K. Sasaki, Nippon Kagaku Kaishi 1999, 355-358 use 1,5-dihydroxy2-pyridone as starting material for the preparation of 5-amino levulinicacid hydrochloride.

Concerning these reaction pathways, both oxidation and reduction stepsare included. The poor yields reached in both processes be in aninconvenient proportion to the expense of the processes. Besides, theprovision of large amounts of the needed pyridine derivatives turn intodifficult.

The processes for the production of 5-amino levulinic acidhydrochloride, listed in the following, are starting with cheap and inlarge quantities available levulinic acid (production on a ton-scale: J.J. Bozell, L. Moens, D. C. Elliott, Y. Wang, G. G. Neuenschwander, S. W.Fitzpatrick, R. J. Bilski, J. L. Jarnefeld, Res. Cons. Recyc. 2000, 28,227-239).

In U.S. Pat. No. 5,987,058, methyl 5-bromo levulinate, which isavailable by bromination of levulinic acid, is transferred to methyl5-N,N-diformylamino levulinate. Subsequent acid catalysed hydrolysisyields 5-amino levulinic acid hydrochloride.

Alternative processes, starting with methyl 5-bromo levulinate have beendescribed. In these processes the bromine at C-5 is exchanged by anucleophilic nitrogen (potassium phthalimide: E. Benedikt, H.-P. Kost,Z. Naturforsch. 1986, 41b, 1593-1594; conversion with sodium azide:H.-J. Ha, S.-K. Lee, Y.-J. Ha, J. W. Park, Synth. Comm. 1994, 24(18),2557-2562). In case of the substitution by an azide, the methyl 5-azidolevulinate is obtained as an heavy oil.

In view of the further conversion to 5-amino levulinic acidhydrochloride by catalytic hydrogenation and simultaneous esterhydrolysis, it has to be guaranteed, that the azido ester is supplied inpure form.

Distillation of the azido ester without any decomposition is notpossible and other purification steps, i.e. chromatographic processes,are very expensive, and therefore not recommendable for the technicalscale.

Further disadvantage of the last described synthetic pathways lie on thedifficult handling of methyl 5-bromo levulinate.

This compound is a liquid with strong lachrymatory properties. Thecompound is a strong skin irritant and further, in the presence oftraces of acid, it has a tendency to the acid catalysed isomerisationinto the compounds methyl 3-bromo-, methyl 3,5-dibromo- and methyl5-bromo levulinate. This circumstance complicates the storage of thecompound.

The substitution of bromine in methyl 5-bromo levulinate by an alkalimetal imide or alkali azide yields sodium bromide as side product, whichmoderate to good solubility in organic solvents, especially loweralkanols, is well-known.

The production of sodium bromide free 5-amino levulinic acidhydrochloride therefore require partially expensive purification steps.

In particular in view of the use of 5-amino levulinic acid hydrochloridefor medical purposes it must be secured, that the drug is very pure andfree as less as possible from impurities deriving from inorganic salts.

A reaction pathway has to be chosen, which yields a pure product by asimple transformation starting with a pure starting material. Sidereactions, whereby side products could be formed, and which have to beseparated from the major product, should not occur.

In comparison to processes, that don't start with levulinic acid, thefunctionalisation with bromine at the C-5-position of levulinic acidoffers the advantage, that 5-amino levulinic acid hydrochloride isavailable without any problems only in two steps starting with puremethyl 5-bromo levulinate. If pure reagents are used, no organic sideproducts arise, which affect the further reaction pathway and have to beseparated expensive.

As side products, only potassium bromide and in case of the hydrolysisof methyl 5-phthalimido levulinate and methyl 5-N,N-Diformyl levulinate,phthalic acid and formic acid, respectively, and methanol are build up,the disposition of which is unproblematic.

A reaction pathway, starting with pure levulinic acid derivatives like5-bromo levulinic acid and particulary 5-chloro levulinic acid,transformation of these carboxylic acids in the next step bysubstitution of the halogen atom with an inorganic azide into 5-azidolevulinic acid, and at least reduction of the azido functionality in5-azido levulinic acid to the amino funtionality, is unknown so far.

The carboxylic acids 5-bromo- and 5-chloro levulinic acid are onlydifficult available on the classic pathway by means of bromination orchlorination of levulinic acid because of the lack of regioselectivityof the halogenation reaction. The desired levulinic acid derivatives areavailable in only poor yields.

But both compounds have the advantageous properties, that they arecrystalline, non-lachrymatory and storable.

The transformation of 5-chloro levulinic acid with potassium azide isespecially advantegeous, because potassium chloride is the only harmlessside product formed.

It is therefore an object of the present invention to provide a compoundand a process for the preparation of this compound, while the employmentof this compound for the preparation of 5-amino levulinic acidhydrochloride overcomes the disadvantages mentioned above.

This object is achieved by the provision of 5-azido levulinic acid.

5-Azido levulinic acid is a so far unknown compound and a new startingcompound for the preparation of 5-amino levulinic acid hydrochloride.

Further object of the present invention is the use of 5-azido levulinicacid as starting compound for the cost-effective and high-yieldpreparation of 5-amino levulinic acid hydrochloride of pharmaceuticalpurity on a technical scale.

The provision of 5-azido levulinic acid allows the creation of animproved production process of 5-amino levulinic acid hydrochloride. Theprocess makes the cost-effective and hield-yield production of 5-aminolevulinic acid hydrochloride of pharmaceutical purity possible.

According to the invention this object is achieved by a process, whichmakes the preparation of 5-amino levulinic acid hydrochloride inpharmaceutical purity and in a four-step-process with an overall yieldof 31-35% possible.

According to the inventive process, cost-effective starting compoundsare used, and products, which have to be disposed are only hydrobromicacid, methanol and potassium chloride.

Surprisingly, a simple way for the preparation of 5-chloro levulinicacid from methyl 5-bromo levulinate was found.

Methyl 5-bromo levulinate, which is obtained by bromination of levulinicacid in methanol in a known manner, reacts quantitatively with aqueoushydrochloric acid under ester hydrolysis and simultaneousbromine/chorine-exchange at position C-5 to give 5-chloro levulinicacid. This transformation is unknown so far.

This compound represents an unlimited storable and excellentlycristallising solid (m.p. 75° C.), which posesses no lachrymatoryproperties.

This compound is better suitable for the transformation with anucleophilic nitrogen like sodium azide, because of the only sideproduct formed is sodium chloride.

Sodium chloride itself is practically unsolulable in organic solventsand nontoxic.

In the following step, the so obtained 5-chloro levulinic acid will bedissolved in a suitable solvent and stirred with one equivalent of asuitable azide, in particular sodium azide.

In particular acetone, but if required also other organic solvents, suchas dipolar aprotic solvents, substituted und unsubstituted amides, cylicand acyclic ethers and the like, may in principle be used as solvent forthe reaction of the 5-chloro levulinic acid with a suitable azide.

However, the work with other solvents having a comparable dissolutionbehaviour, in particular solvents of high polarity, should not be ruledout.

As a new key compound, the so far unknown 5-azido levulinic acid arisesin quantitative yield by means of nucleophilic substitution.

This new key compound represents a colorless, crystalline (m.p. 70-71°C.) and an unlimited and without any decomposition storable compound, ifprepared according to the following process. The substance contains noinorganic material, it is not sensitive to impact, and it can be safelyhandled at room temperature.

Because of an uncomplete bromine/chlorine-exchange, 5-chloro levulinicacid may obtain as many as 8% of 5-bromo levulinic acid. But, thepresence of small amounts of 5-bromo levulinic acid does not disturb thefurther reaction pathway, because this compound also reacts with asuitable inorganic azide, in particular sodium azide, in acetone assolvent with clean formation of 5-azido levulinic acid.

The conversion of 5-bromo levulinic acid, which was prepared on adifferent pathway, with sodium azide in acetone, after crystallisationfrom an organic solvent resulted in the formation of 5-azido levulinicacid in nearly quantitative yield. The compound was free of inorganicsalts.

In the following step, the key compound 5-azido levulinic acid will bereduced to 5-amino levulinic acid hydrochloride without anydifficulties. The reduction is preferably carried out as a catalytichydrogenation in the presence of a metal catalyst (preferably palladiumor platinum on a suitable carrier, such as active carbon) in aqueoushydrochloric acid without any arise of undesireable organic by-products.The catalyst can be regenarated. 5-Amino levulinic acid hydrochloride isobtained absolutly pure with an overall yield of 31-35% (starting fromlevulinic acid).

According to the present invention, the problem is solved by making5-azido levulinic acid available, and providing a process for itspreparation. The preparation process of 5-azido levulinic acid impliesthe conversion of methyl 5-bromo levulinate and/or methyl 5-chlorlevulinate with aqueous hydrochloric acid. As a result of an incompletebromine/chlorine-exchange at the C-5 postion, a mixture of 5-chloro- and5-bromo levulinic acid is obtained. The obtained mixture of 5-chloro-and 5-bromo levulinic acid, 5-chloro levulinic acid, and pure 5-bromolevulinic acid will be transferred into 5-azido levulinic acid byconversion of the compounds with an nucleophilic azide.

It is preferred, according to the present invention, to carry out theconversion with an azide in a polar solvent, especially acetone, anC₁-C₄-alkanol or water as the reaction medium.

Furthermore, according to the present invention, the problem is solvedby using 5-azido levulinic acid for the preparation of 5-amino levulinicacid hydrochloride, where 5-azido levulinic acid is transferred to5-amino levulinic acid hydrochloride by catalytic hydrogenation.

In particular it is preferred to carry out the catalytic hydrogenationin aqueous hydrochloric acid, to remove the hydrogenation catalyst, toremove the solvent and excess hydrochloric acid by distillation, and toobtain 5-amino levulinic acid hydrochloride by crystallisation from2-propanol or tert-butyl methylether/methanol.

Surprisingly it was found also, that 5-azido levulinic acid possesesexplosive properties. Because of its chemical constitution, onlynontoxic gases, namely nitrogen and carbon oxide, will be released asreaction substances. The released amount of gas is very large and willbe increased by the exothermic reaction during explosion. 5-azidolevulinic acid is sensitive to impact and detonates already at an impactenergy of 40 J.

For this reason, 5-azido levulinic acid is especially suitable aspriming fuse and as explosive for the operation of airbags in the motorvehicle industry.

The following examples explain the invention.

EXAMPLE 1

Preparation of 5-Chloro levulinic acid: A solution of 1 g (4.78 mmole)of methyl 5-bromo levulinate in 20 ml of 3 M hydrochloric acid wasstirred at 70° C. until the reaction was finished (24 h, ¹H-NMR controlspectra showed only product signals). The solvent, excess hydrochloricacid, hydrobromic acid, and methyl alcohol were removed by distillationin in vacuo. To the residue 20 ml of methylene chloride was added andthe resulting solution was dried over sodium sulfate. Evaporation of thesolvent yielded 702 mg of a pale yellow solid. The solid was dissolvedin 2 ml of tert-butyl methylether. Petroleum ether (40-60° C.) was addeddropwise until crystallisation occured. The mixture was stirred for 0.5h at ambient temperature and the crystals were filtered off.

Yield: 684 mg, 95% Melting point: 75° C.; an x-ray analysis study of thecrystals confirms the structure of the compound. Elemental analysis:Calcd. C, 39.89, H, 4.69; Found C, 39.35, H, 4.67. IR (KBr): ν(cm⁻¹)=3500-2100, 1700 (C═O), 1440, 1410, 1370, 1330, 1290, 1210, 1140,1090, 1030, 950, 865, 765, 730, 610. ¹H-NMR (CDCl₃, 200 MHz): δ(ppm)=2.70 (t, ³J=6.7 Hz, 2H), 2.96 (t, ³J=6.7 Hz, 2H), 4.14 (s, 2H),8.8 (br. s, 1H). ¹³C-NMR (CDCl₃, 50.3 MHz): δ (ppm)=27.7 (HOOC—CH₂),34.0 (CH₂—CH₂—C═O), 48.0 (CH₂—Cl), 178.4 (COOH), 201.2 (C═O).

EXAMPLE 2

Preparation of a mixture of 5-chloro levulinic acid and 5-bromolevulinic acid: A mixture of 1 g (4.78 mmole) of methyl 5-bromolevulinate in 20 ml of 3 M hydrochloric acid was stirred for 12 h at 70°C. The solvent, excess hydrochloric acid, hydrobromic acid, and methylalcohol was removed by distillation in vacuo. To the residue 20 ml ofmethylene chloride was added and the resulting solution was dried oversodium sulfate. Evaporation of the solvent yielded 740 mg of a paleyellow solid. The solid was dissolved in 2 ml of tert-butyl methylether.Petroleum ether (40-60° C.) was added dropwise until crystallisationoccured. The mixture was stirred for 0.5 h at ambient temperature andthe crystals filtered off.

Yield: 700 mg, 95% ¹H-NMR: After integration of the 5-CH₂-proton signalsof the mixture of 5-chloro levulinic acid and 5-bromo levulinic acid aratio of 92:8 was found.

EXAMPLE 3

Preparation of 5-azido levulinic acid from 5-chloro levulinic acid:5-Chloro levulinic acid (prepared as described in Example 1) and sodiumazide were reacted with one another in a molar ratio of 1:1 in acetone.The reaction mixture was stirred at 50° C. until the end of the reaction(¹H-NMR control spectra showed only product signals). To the reactionmixture 20 ml of methylene chloride was added, the solid was filteredoff, the filtrate was washed with 3 M aqueous sodium chloride and driedover sodium sulfate. Evaporation of the solvent yielded a pale yellowoil in quantitative yield. Crystalisation of the residue from methylenechloride/petroleum ether (40-60° C.) yielded pale yellow needlesconsisting of 5-azido levulinic acid.

Yield: 700 mg, 95% Melting point: 70-71° C. Elemental analysis: Calcd.C, 38.22; H, 4.49; N, 26.74; Found C, 38.39; H, 4.59; N, 26.07. IR(KBr): ν (cm⁻¹)=3350-2350, 2090 (N₃), 1725 (C═O), 1415, 1400, 1370,1340, 1285, 1260, 1230, 1170, 1080, 1040, 1000, 930, 885, 830, 800, 685,630. ¹H-NMR (CDCl₃, 200 MHz): δ (ppm)=2.70 (s, 4H), 4.02 (s, 2H), 8.3(br. s, 1H). ¹³C-NMR (CDCl₃, 50.3 MHz): δ (ppm)=27.4 (HOOC—CH₂), 34.1(CH₂—CH₂—C═O), 57.5 (CH₂—N₃), 177.3 (COOH), 202.7 (C═O).

EXAMPLE 4

Preparation of 5-azido levulinic acid from a mixture of 5-chlorolevulinic acid and 5-bromo levulinic acid: A mixture of 5-chloro and5-bromo levulinic acid (0.5 g, prepared as described in Example 2) andsodium azide were reacted with one another in a molar ration of 1:1 inacetone. The reaction mixture was stirred at 50° C. until the end of thereaction (¹H-NMR control spectra showed only product signals). An amountof 20 ml of methylene chloride was added, the solid was filtered off,the filtrate was washed with 3 M aqueous sodium chloride and dried oversodium sulfate. Evaporation of the solvent yielded a yellow oil inquantitative yield. Crystalisation of the residue from methylenechloride/petroleum ether (40-60° C.) yielded pale yellow needlesconsisting of 5-azido levulinic acid.

Yield: 510 mg, 95%; the physical and spectroscopic data are in agreementwith those obtained from the material prepared according to Example 3.

EXAMPLE 5

Preparation of 5-azido levulinic acid from 5-bromo levulinic acid:5-bromo levulinic acid (prepared as described in Example 7) wasdissolved in acetone. To the resulting solution was added sodium azideto a molar ratio of 1:1 (5-bromo levulinic acid:sodium azide) and thereaction mixture was stirred at 50° C. until the end of the reaction(¹H-NMR control). To the reaction mixture 20 ml of methylene chloridewas added, the solid was filtered off, the filtrate was washed with 3 Maqueous sodium chloride and dried over sodium sulfate. Evaporation ofthe solvent yielded a pale yellow oil in quantitative yield.Crystalisation of the residue from methylene chloride/petroleum ether(40-60° C.) yielded pale yellow needles consisting of 5-azido levulinicacid.

Yield: 390 mg, 97% Melting point: 70-71° C.; the physical andspectroscopic data are in agreement with those obtained from theprepared according to Example 3.

EXAMPLE 6

Preparation of 5-amino levulinic acid hydrochloride by hydrogenation of5-azido levulinic acid: 5-azido levulinic acid otained according toExample 3 was dissolved in 3 M hydrochloric acid, a hydrogenationcatalyst (palladium on carbon) was added and the reaction mixture washydrogenated for 5 h while passing in hydrogen at a pressure of 6 bar.By monitoring the hydrogenation it was found that the hydrogenation wascompleted quantitatively after 5 h (¹H-NMR control spectra showed onlyproduct signals). The catalyst was filtered off from the clear andcolorless solution, and the reaction medium, hydrochloric acid, wasremoved by distillation in vacuo. To the resulting viscous, colorlessresidue 4 ml of 2-propanol was added while stirring. Alternatively, theresidue was dissolved in 5 ml of methanol and an amount of 5 ml oftert-butyl methylether was added while stirring. In both cases colorlesscrystals were formed after a short time, which were filtered off. Theobtained crystals were washed with acetone and dried in vacuo.

Yield: 709 mg, 95% Melting point: 150-151° C.; melting point data ofvarious producers: 144-151° C.; Merck: 150-156° C.; Fluka: ˜150° C.(decomposition); Aldrich: 156° C. (decomposition); Acros Organics156-158° C. (decomposition).

The NMR data (A. Nudelman and A. Nudelman, Synthesis 1999, 4, 568-570)and chromatographic data (C. Herdeis, A. Dimmerling, Arch. Pharm. 1984,317, 304-306) are in agreement with those given in the literature.

EXAMPLE 7

Preparation of 5-bromo levulinic acid: Levulinic acid (5.0 g, 43.1mmole) was dissolved in 50 ml of carbon tertrachloride in a three-neckedflask with a mechanical stirrer, a dropping funnel, a reflux condenser,and an internal thermometer. To the reaction mixture bromine (6.88 g,43.1 mmole) was added dropwise during 0.5 h at ambient temperature.After decoloration of the orange reaction mixture 50 ml of water wereadded. The organic layer was separated, washed with brine, and driedover magnesium sulfate. Evaporation of the solvent yielded a yellow oil.From 50 ml of ether/petroleum ether (40-60° C.) colorless crystals areformed consisting of pure 5-bromo levulinic acid.

Yield: 900 mg, 9.5% Melting point: 79-80° C. IR (KBr): ν(cm⁻¹)=3500-2100, 1700 (C═O), 1430, 1400, 1350, 1300, 1280, 1240, 1100,1050, 970, 920, 860, 760, 720, 610. ¹H-NMR (CDCl₃, 200 MHz): δ(ppm)=2.70 (t, ³J=6.7 Hz, 2H), 2.96 (t, ³J=6.7 Hz, 2H), 3.95 (s, 2H),8.5 (br. s, 1H). ¹³C-NMR (CDCl₃, 50.3 MHz): δ (ppm)=28.0 (HOOC—CH₂),34.1 (CH₂—CH₂—C═O), 33.9 (CH₂—Cl), 178.0 (COOH), 200.4 (C═O).

1. 5-azido levulinic acid.
 2. Process for the preparation of5-azidolevulinic acid, wherein (a) methyl 5-bromo levulmate and/ormethyl 5-chloro levulinate is reacted with aqueous hydrochloric acid andas a result of an incomplete bromine/chlorine exchange at theC-5-postion a mixture of 5-chloro levulinic acid and 5-bromo levulinicacid is obtained, and (b) the obtained mixture of step (a) is convertedto 5-azido levulinic acid by conversion with a nucleophilic azide. 3.Process according to claim 2, wherein in stage (b) the conversion withan azide is carried out in a reaction medium consisting of a polarsolvent.
 4. Process according to claim 2, wherein in stage (b) an alkalimetal azide is used as nucleophilic azide.
 5. A method of preparing5-amino levulinic acid hydrochloride, wherein 5-azido levulinic acid isconverted into 5-amino levulinic acid hydrochloride by catalytichydrogenation.
 6. The method according to claim 5, wherein (a) thecatalytic hydrogenation ist carried out in aqueous hydrochloric acid,(b) the solvent and excess hydrochloric acid is seperated and (c)5-amino levulinic acid hydrochloride is obtained by cristallisation from2-propanol or t-butyl methyl ether/methanol.
 7. Process according toclaim 2, wherein in stage (b) a sodium azide is used as nucleophilicazide.